For normal activities that produce rewards, there is a rapid habituation of the circuits involved and the behaviors will wane. However, for addictive drugs habituation does not occur and dopamine release persists despite repetitive trials. Upon withdrawal of the drug, a decrease of dopamine levels in the nucleus accumbens results, and this has been observed for opioids, cannabinoids, alcohol, amphetamines, and nicotine (Cami & Farre (2003) N. Engl. J. Med. 349:975). This loss of dopamine accounts for the withdrawal syndromes observed with these drugs. The prototype opioid drug is morphine. It produces many effects typical of most opioids including analgesia, euphoria, nausea, and respiratory depression. Repeated use of opioids produces physical dependence and tolerance. These manifestations of opioid use are due to the three recognized types of opioid receptors that are members of the GPCR family, the mu (μ), delta (δ), and kappa (κ) subtype receptors. While stimulation of the mu and delta receptors increases dopamine release in the nucleus accumbens, κ opioid (KOP) receptor activation by its endogenous ligand dynorphin-A reduces extracellular dopamine. It has been suggested that stimulation of KOP receptor by endogenous opioids like dynorphins will produce an aversive state and thereby counter the effects of rewarding and addictive compounds like alcohol, cocaine and nicotine. Moreover, exogenous KOR agonists have also been observed to attenuate drug-taking behavior (Prisinzano, et al. (2005) AAPS J. 7:E592; Xuei, et al. (2006) Mol. Psychiatry 11:1016; Hasebe, et al. (2004) Ann. NY Acad. Sci. 1025:404; Metcalf & Coop (2005) AAPS J. 7:E704). However, it may be difficult to strike a balance between opposing the sense of reward gained by drugs of abuse and producing an aversive state; therefore, activation of the KOP receptor may not be therapeutically preferable. Although these statements appear contrary, KOP receptor agonists can both alleviate drug self-administration in animal models (most likely via dopamine regulation) and also trigger relapse. This conflicting dual action of KOP receptor agonists alludes to the complex physiological role of KOP receptors and underscores the need for a variety of chemical tools to facilitate their further investigation.
Intracranial self-stimulation has become a useful means of assessing reward thresholds in rodents and nonhuman primates. In essence, an animal will press a lever to electrically stimulate the brain via implanted probes. This “self stimulation” will be performed to a certain extent in training and that extent is an indication of the animal's “reward threshold.” Administration of “drugs of abuse” has been shown to decrease this reward threshold such that the animal will seek less stimulation to achieve the desired effect. This model paradigm has been likened to positive hedonic states produced by drugs of abuse in human addicts. In rodents, the direct activation of KOP receptor using selective agonists increases reward thresholds (mimicking the withdrawal state) and creating a “depressive-like” state (where more self stimulation is required to achieve the desired effect). Treatment with antagonists has been shown to restore reward thresholds in this model (Glick, et al. (1995) Brain Res. 681:147; Bruijnzeel (2009) Brain Res. Rev. 62:127). The restoration of reward thresholds may be a very important step in drug abuse treatment as drug cessation is strongly negatively reinforced by aversive feelings, which may be due to an increased reward threshold. Therefore, the development of KOP receptor antagonists would be particularly beneficial in “resetting” this threshold. Furthermore, since an increased reward threshold may manifest as a “depressive state,” then KOP receptor antagonists can also be beneficial for the treatment of depressive disorders.
There are molecules known to activate or inhibit the KOP receptor, including salvinorin A, ketazocine, U-50,488, 5′-guanidinonaltrindole and JDTic ((3R)-7-Hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide). Many of these molecules are either direct derivatives of opium alkaloids such as GNTI (5′-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2′,3′-indolomorphinan; Jones, et al. (1998) J. Med. Chem. 41:4911) or contain structural elements borrowed from these alkaloids, as can be observed for JDTic (Thomas, et al. (2001) J. Med. Chem. 44:2687-2690) and ketazocine (Merz & Stockhaus (1979) J. Med. Chem. 22:1475-1483). One consequence of this legacy is that many of the established potent and selective molecules are structurally complex, containing multiple stereocenters and requiring lengthy synthetic routes to construct modified analogues. The natural product Salvinorin A (Roth, et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99:11934-11939) is unique as a potent, non-nitrogenous KOP receptor ligand. While not an alkaloid, Salvinorin A is equal in structural complexity to any of the isolated opiates. Even the widely utilized, simplified agonist compound, U-50,488 (VonVoigtlander & Szmuszkovicz (1982) J. Med. Chem. 25:1125-1126) contains two chiral centers.
Currently, there are currently no approved agents or compounds for treating the altered reward pathways associated with drug addiction (Prisinzano (2005) supra). Accordingly, there is a need in the art for effector chemotypes (possessing novel patterns of binding toward the KOP receptor) that can be readily synthesized for use in analyzing the KOP receptor as well as in therapeutic methods.